The experiments of this proposal address a novel approach towards vaccination against HIV disease, namely: to create a vaccine that will prevent, rather than to elicit, a robust immune response against the virus. The rationale for this approach is prompted by several observations: on the one hand, there is no clear evidence that a robust immune response will be protective against HIV; on the other hand, it seems clear that HIV replication and spread are fostered, not hindered, by pro-viral effects associated with immune activation and inflammation. These observations prompt an alternative hypothesis: the best response to HIV might be no response at all, i.e., an effective vaccine should induce tolerance to HIV instead. Tolerance to HIV may result in abortive infection because, absent the effects of inflammation that normally drive viral replication and spread (e.g., the proviral impact of certain cytokines and of enhanced rates of cell proliferation and migration), infected cells may simply be cleared. To test this hypothesis, we propose to study lentiviral infection in the context of hosts made specifically tolerant to lentivirus. Given new findings that we have made about the induction of tolerance in the human fetus, we will rely upon a well-characterized experimental model (SIV infection of the rhesus macaque) to induce tolerance by one of two proven routes (injection of antigen in utero and oral administration of antigen at birth) or by a combination thereof. In each case, we postulate that antigen- specific tolerance will be induced because a tolerogenic fetal T cell lineage will respond. We will then assess whether newborns rendered tolerant to SIV are more (or less) able to clear a pathogenic SIV challenge. Data from these experiments will greatly expand our understanding of tolerance induction in the fetus and the newborn. We will learn whether the fetal macaque, like the fetal human, can mount a tolerogenic response against exogenous agents that includes active suppression by Treg. We will also, for the first time, be able to explore the mechanics of oral tolerance induction in the nonhuman primate newborn. When this basic knowledge about tolerance induction is then studied in the context of pathogenic SIV challenge, we might also learn: (a) why the overwhelming majority of babies born to HIV-infected mothers are spared infection and (b) how to create a vaccine against HIV that is effective because it induces a tolerogenic as opposed to an immunostimulatory antiviral response. These experiments are relevant to public health for two reasons. First, they may provide proof-of- concept data for the formulation of an entirely new type of vaccine approach against HIV. Secondly, the approach used here for HIV might also prove useful for protective vaccination against other chronic infectious diseases (e.g., tuberculosis and malaria) that often co-exist with HIV as well as against other illnesses (e.g., autoimmune diseases) or conditions (e.g., organ transplantation) in which the induction of antigen-specific tolerance might be beneficial.